Proper salivary gland function is critical for the maintenance of oral health and physiological well-being. Saliva functions to moisten the oral tissues as an aid for speech, as a solvent important for taste, and as a masticatory wetting agent/lubricant important in swallowing food. Saliva contains inorganic and organic components important for the health of the oral soft tissues and the teeth. Salivary gland dysfunction resulting in diminished salivary output and/or altered salivary composition results in the subjective sensation of dry mouth (xerostomia). Saliva also plays an important role in host defense and is a major contributor of the innate host defense of the upper gastrointestinal tract. In addition, the salivary glands are a major component in the mucosal immune system of the oral cavity that confers antigen-specific immunity to oral and mucosally-acquired pathogens. Although it has long been known that the salivary gland is an important effector organ in the oral cavity, the issue of whether the salivary gland can function as an inductive site during an immune response has not been addressed. If the salivary gland is an inductive site in addition to an effector site, antigenic stimulation of the salivary gland may be sufficient to induce immunity to viruses and other pathogens even at distal mucosal sites. Understanding the immunobiology of the salivary glands is also of particular interest because of rapidly developing progress in gene therapy and tissue engineering as it relates to the salivary gland. The ability to "re-engineer" the salivary gland via gene transfer in vivo with the resultant in situ restoration of fluid secretion and to utilize salivary endocrine secretory pathways for systemic gene therapeutics provides additional reason for gaining a better understanding of how salivary gland immunity interacts with the expression of transferred gene(s), especially because the transferred gene(s) are frequently expressed utilizing recombinant viral vectors. Murine cytomegalovirus (MCMV) infections have served as a tool for investigating salivary gland immunity. In addition, MCMV infections have already been used for some time as models for human CMV infection. Human CMV infections are common but do not lead to significant disease in immunocompetent healthy adults. However, in immunocompromised patients (transplant recipients or AIDS patients) CMV infection becomes a serious complication and source of mortality. Therefore, understanding the immune responses to MCMV infections can lead to a better understanding of the pathogenesis of CMV infections in humans. In addition, human CMV can be spread through oral and respiratory secretions and through sexual transmission. This makes investigating the mucosal responses to MCMV, in particular, relevant to infection in humans. In this application, we have developed a new model of focused salivary gland infection utilizing MCMV. Aim #1 will investigate the hypothesis that the salivary gland can function as an inductive site in the context of the common mucosal immune system. Aim #2 will investigate the hypothesis that the salivary gland generates functionally protective immunity to MCMV infection at both mucosal and systemic sites.